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Clinical Study

Oncology 2007;72:255–260 DOI: 10.1159/000113017

A Phase II Study of Cisplatin, Ifosfamide and Epirubicin Combination Chemotherapy in Adults with Nonmetastatic and Extremity Osteosarcomas

Mert Basaran a E. Sevil Bavbek a Sezer Saglam a Levent Eralp b Burak Sakar a

Ata Can Atalar b Bilge Bilgic c Harzem Ozger b Haluk Onat d

a Department of Medical Oncology, Institute of Oncology, and Departments of b Orthopedic Surgery and c Pathology, Istanbul Medical Faculty, Istanbul University, Istanbul , and d Anadolu Saglik Grubu, Izmit , Turkey

apy was 26 and 37%, respectively. The 5-year disease-free and overall survival rates were 41.9% (95% CI 33.6–50.2) and 48.2% (95% CI 39.6–56.8). The most prominent grade 4 toxic-ity was neutropenia occurring in 32% of patients. The lungs were the most frequent site of relapse (32%). Conclusions: The combination of cisplatin, ifosfamide and epirubicin is an active, reasonably well-tolerated regimen without grade 3 or 4 cardiac toxicity in patients with nonmetastatic extrem-ity osteosarcoma and deserves further investigation in the context of prospective phase III trials.

Copyright © 2008 S. Karger AG, Basel

Introduction

Osteosarcoma is a rare malignancy, accounting for less than 0.5% of all cancers [1] . The prognosis of osteo-sarcoma patients has improved over the last 2 decades with the introduction of aggressive combination chemo-therapy as part of the multimodality management. In pa-tients with localized resectable primary osteosarcoma, neoadjuvant and adjuvant chemotherapies have been the standard of care based on the survival benefit data from randomized clinical trials [2, 3] . Cisplatin, anthracyclines and ifosfamide have all been proven effective in the treat-ment of osteosarcoma and thus form the backbone of

Key Words

Combination chemotherapy � Cisplatin � Epirubicin � Ifosfamide � Osteosarcoma

Abstract

Background: Osteosarcoma is a rare malignancy, and pa-tients with this disease benefit from adjuvant chemothera-py. While cisplatin, anthracyclines and ifosfamide are the most commonly used agents in the treatment of osteosar-coma, a search for the best combination with higher efficacy and minimal toxicity continues. We planned to evaluate the efficacy of epirubicin combined with cisplatin and ifos-famide in patients with localized primary osteosarcoma. Methods: Patients with nonmetastatic extremity osteosar-coma who were older than 15 years were included in the study. The preoperative chemotherapy regimen consisted of epirubicin 90 mg/m 2 , cisplatin 100 mg/m 2 on day 1 and ifosfamide 2.0 g/m 2 /day with an equivalent dose of mesna on days 2–4, repeated every 21 days. Six cycles of this com-bination regimen were administered (3 cycles prior to sur-gery and 3 cycles postoperatively). Results: Forty-five pa-tients with localized osteosarcoma entered this phase II trial. Median follow-up was 64 months. Thirty-two patients (84%) received the assigned 6 cycles of chemotherapy. Complete and good histological response to neoadjuvant chemother-

Received: July 13, 2007 Accepted after revision: July 19, 2007 Published online: January 10, 2008

Oncology

Mert Basaran, MD Ahmet Refik Sokak Ceylan apt. 19/13 Ciftehavuzlar, Istanbul (Turkey) Tel. +90 542 243 2417, Fax +90 216 368 7187, E-Mail basaranm@istanbul.edu.tr

© 2008 S. Karger AG, Basel0030–2414/07/0724–0255$23.50/0

Accessible online at:www.karger.com/ocl

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combination regimens for osteosarcoma [4–6] . Among anthracyclines, doxorubicin has been the most common-ly used agent in the osteosarcoma regimens. It is well known that epirubicin has a lower toxicity profile than doxorubicin in terms of cardiac morbidity. In this phase II study, we planned to use a combination chemotherapy involving epirubicin instead of doxorubicin for patients with localized primary osteosarcoma and aimed to eval-uate the efficacy of epirubicin combined with cisplatin and ifosfamide. Late cardiac toxicity and the survival im-pact of this combination regimen on patients with non-metastatic osteosarcoma were our secondary endpoints.

Patients and Methods

Patient Selection and Evaluation Thirty-eight consecutive patients with osteosarcoma were en-

rolled in this study between 1993 and 2002. The patient charac-teristics are shown in table 1 . All patients were 15 years of age or older. Eligibility criteria included histological diagnosis of osteo-sarcoma or primary malignant fibrous histiocytoma of the bone, no previous chemotherapy, adequate renal function (defined by glomerular filtration rate of 6 60 ml/min), adequate hepatic func-tion (defined as total bilirubin ̂ 2 mg/dl), absolute neutrophil count 1 1,500/ � l and platelet count 1 100,000/ � l, as well as an Eastern Cooperative Oncology Group performance score of 0–2. Exclusion criteria included patients with nonextremity tumors, soft tissue osteosarcomas or active infection and patients older than 60 years. This study has been approved by our institutional ethic committee, and all patients provided written informed con-sent before enrollment.

Before the first treatment, all patients had a complete history and physical examination performed. Baseline imaging studies included a computed tomography scan of the chest, whole-body bone scintigraphy and intravenous contrast-enhanced magnetic resonance imaging of the primary tumor for all patients. Cardiac function was assessed by echocardiography and electrocardiog-raphy prior to first chemotherapy and at least 2 years after com-pletion of chemotherapy. Patients were monitored with weekly complete blood cell counts until recovery from hematopoietic toxicity and 3-weekly physical examination. Renal (serum creati-nine) and hepatic function (ALT, lactate dehydrogenase, alkaline phosphatase and bilirubin) tests and electrolytes (including cal-cium, magnesium and phosphorus) were repeated before each cy-cle of therapy.

Chemotherapy Regimen, Toxicity and Dose Modifications The preoperative chemotherapy regimen consisted of epirubi-

cin 90 mg/m 2 (15 min infusion), cisplatin 100 mg/m 2 (2 h infu-sion), with pre- and posthydration and mannitol diuresis on day 1, and ifosfamide 2.0 g/m 2 /day (4 h infusion), with an equivalent dose of mesna on days 2–4, repeated every 21 days. Three cycles of chemotherapy were administered prior to surgery. Patients re-ceived 3 cycles of the same preoperative regimen postoperatively, but with 4-week intervals.

Chemotherapy Toxicity Was Recorded by Using the National Cancer Institute Criteria Complete blood counts and differentials were assessed weekly

during chemotherapy. Chemotherapy was delayed for 1 week if the neutrophil count remained ! 1,000/mm 3 or the platelet count remained ! 100,000/mm 3 on days 22 and 29. For patients who ex-perienced prolonged neutropenia ( 1 5 days) or febrile neutrope-nia, granulocyte-colony stimulating factor was added for all sub-sequent cycles. Cisplatin dose was adjusted based on the serum creatinine level and/or the creatinine clearance by the Cockcroft formula measured before each cycle. Cisplatin dose was reduced to 70 mg/m 2 if the creatinine clearance was between 50 and 75 ml/min, or if serum creatinine was between 1.5 and 2.0 mg/dl.No further cisplatin is administered if the serum creatinine was 1 2.0 mg/dl or the creatinine clearance was ! 50 ml/min.

Surgery The primary aim of surgery was to perform a limb salvage op-

eration with radical or wide negative tumor margins. Amputation of the extremity was another surgical treatment option for which extremity sparing surgery was not possible.

Response Criteria Histological response to neoadjuvant chemotherapy was as-

sessed by estimating the percentage necrosis in the resected spec-imen. Complete histological response was defined as no viable tumor; good histological response was defined as having percent-

Table 1. Patient characteristics

Characteristics Patients

n %

Age, yearsMedian 22Range 15–41

SexMale 25 66Female 13 34

Performance status WHO0–1 35 92≥2 3 8

Tumor locationTibia 16 42Femur 14 36Humerus 6 16Radius 1 3Fibula 1 3

Tumor size (greatest dimension)0.1–5 cm 4 115.1–10 cm 13 34>10 cm 21 55

Histology (subtype)Classic 34 90Pleomorphic 2 5Telengiectasia 2 5

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Oncology 2007;72:255–260 257

age necrosis between 6 90 and ! 100%, and poor histological re-sponse was defined as having ! 90% necrosis in the resected spec-imen.

Follow-Up Follow-up duration was calculated from the first day of che-

motherapy to either the day of death or the day of the last visit. Patients were evaluated with magnetic resonance imaging for the primary tumor location and a computed tomography scan of the thorax every 3 months for the first 2 years, every 4–6 months for the third year, every 6 months until the fifth year, and annually thereafter.

Statistical Method The primary end point of the study was the response rate, and

secondary endpoints were late cardiac toxicity and survival. The response rate was assessed based on histologic criteria. Survival was calculated using the Kaplan-Meier method. Disease-free sur-vival was calculated from the time of the start of chemotherapy to the time of recurrent disease at any site. Overall survival was calculated from the time of the start of chemotherapy to the date of last follow-up or death. The analysis was performed by using SPSS edition 10.5 statistical software (SPSS Inc., Chicago, Ill., USA).

Results

Between 1993 and December 2002, 45 patients with localized osteosarcoma entered this phase II trial. A total of 7 patients were ineligible; 3 patients were less than 15 years old, 2 patients had nonextremity osteosarcoma, and 2 patients had inadequate renal and hepatic function tests. The median age was 22 years (range 15–41). There

were 25 males and 13 females. Anatomic distribution of the primary tumor was as follows: tibia (n = 16), fe-mur (n = 14), humerus (n = 6), radius (n = 1) and fibula (n = 1). Patient characteristics are shown in table 1 .

Treatment Patients received a median of 3 cycles (range 1–4) of

preoperative chemotherapy. Two patients received 4 cy-cles of chemotherapy prior to surgery due to the delays in surgery. One patient received only 1 cycle of chemother-apy due to clinical progression of the disease. Two pa-tients received 2 cycles of chemotherapy because they were very anxious about the time elapsed between preop-erative chemotherapy and surgery.

Toxicities The chemotherapy regimen was well tolerated. Thir-

ty-two patients (84%) received the assigned 6 cycles of chemotherapy. One-hundred and eighty out of 221 cycles (81%) of chemotherapy were evaluable for toxicity. Pa-tients received a median of 6 cycles of the 3-drug regi-men. Six patients required early discontinuation of che-motherapy. The reasons for discontinuation were grade4 thrombocytopenia in 1 patient, methicillin-resistant Staphylococcus aureus graft infection in 1 patient, che-motherapy refusal in 2 patients and chemotherapy intol-erance in 2 patients.

The most prominent grade 4 toxicity was neutrope-nia occurring in 32% of patients ( table 2 ). There were 9 cases (24%) of febrile neutropenia requiring antibiotic therapy and granulocyte colony-stimulating factor sup-port. There was no other grade 4 toxicity experienced by more than 10% of patients. Dose reduction was per-formed in 3 patients due to thrombocytopenia, in 3 pa-tients due to febrile neutropenia and in 1 patient due to chemotherapy intolerance. Dose delays of more than 1 week were required for 19 patients, mostly due to neu-tropenia. Three patients (8%) required platelet transfu-sions and 4 patients (11%) required packed red blood cell transfusions.

In addition, 21 (55%) other patients experienced re-versible grade 3 nonhematological toxicity. One patient (3%) had reversible grade 3 nephrotoxicity. No grade 3–4 bladder, ototoxicity and acute cardiac toxicity were ob-served. Grade 2 cardiac toxicity was observed in 8 (21%) of 38 patients. There was asymptomatic left ventricular diastolic dysfunction with resting ejection fraction be-tween 40 and 50% in 3 patients, hypotension with brief fluid replacement in 2 patients, supraventricular arrhyth-mia in 2 patients and palpitation in 1 patient. Fourteen

Table 2. Toxicity due to chemotherapy in 38 patients

Grade

I II III IV

Hematologic toxicityAnemia 10 (26) 8 (21) 13 (34) 3 (8)Neutropenia 1 (3) 10 (26) 15 (39) 12 (32)Thrombocytopenia 11 (29) 5 (13) 3 (8) 3 (8)

Fatigue 10 (26) 16 (42) 12 (32)Mucositis 11 (29) 13 (34) 4 (11) 0Diarrhea 11 (29) 7 (18) 1 (3) 0Nausea 4 (11) 20 (53) 12 (32) 2 (5)Vomiting 22 (58) 11 (29) 3 (8) 2 (5)Renal toxicity 9 (24) 2 (5) 1 (3) 0Febrile neutropenia 9 (24)Cardiac toxicity 8 (21) 0 0

Figures in parentheses are percentages.

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patients (37%) experienced grade 3 or 4 nausea or vomit-ing. One patient (3%) experienced grade 3 diarrhea, and 4 (11%) patients experienced grade 3 mucositis.

There was no late cardiac toxicity or nephrotoxicity exceeding grade 2. There was also no treatment-related death in this study.

Surgery Limb-sparing surgery was performed on 33 (87%) pa-

tients. The resulting tissue defect was reconstructed by medullary endoprosthesis in 31 (94%) patients. Primary amputation was indicated in 5 patients due to the size and/or anatomic localization of the tumor. Two patients (5.2%) with prosthetic replacement had an infection, and their extremities were amputated subsequently because the infection was unresponsive to medical and surgical

therapies. Local relapse occurred in 2 patients (5.2%), and those patients subsequently underwent amputation of their extremity. In total, 29 patients (76%) had their ex-tremities spared.

Histological Response Rates Complete histological response to neoadjuvant che-

motherapy was 26% assessed by the percentage necrosis in the resected specimen. Good histological response was 37%, and there was poor histological response ( ! 90% ne-crosis) in 37% of the patients ( table 3 ).

Survival Median follow-up was 64 months (range 4–132); 2

(5%) patients were lost to follow-up. Nineteen patients (50%) had their disease relapsed and 16 patients died with

Table 3. Histologic response rates in 38 patients with osteo-sarcoma

Response After chemotherapy

n %

Complete 10 26Good 14 37Poor 14 37

Table 4. Site of progression or recurrent disease

Site n %

Local 0 0Lung 12 32Bone 2 5Local and lung 1 3Local and bone 1 3

12010896847260483624120Months

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CensoredSurvival function

Disease-free survival

0

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0.4

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0.8

1.0

12010896847260483624120Months

Cum

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surv

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Overall survival

0

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0.4

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Fig. 1. Disease-free survival curve using Kaplan-Meier method. Fig. 2. Overall survival curve using Kaplan-Meier method.

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disease progression. The lungs were the most frequent site of relapse (32%) ( table 4 ).

The 5-year disease-free and overall survival rates were 41.9% (95% CI 33.6–50.2) and 48.2% (95% CI 39.6–56.8), respectively ( fig. 1, 2 ).

Discussion

This trial was designed to test the efficacy of epirubi-cin in combination with cisplatin and ifosfamide in pa-tients with nonmetastatic osteosarcoma. Our data dem-onstrated that the combination of cisplatin, ifosfamide and epirubicin is an active regimen in terms of histologi-cal response rate and is generally well tolerated without grade 3 or 4 cardiac toxicity.

The longer follow-up of the study should be taken into consideration while interpreting the disease-free surviv-al and late cardiac toxicity. Myelosuppression was the major toxicity; grade 3 or 4 neutropenia, anemia and thrombocytopenia were reported in 71, 42 and 16% of the cases, respectively. Despite the high frequency of myelo-suppression, only 24% of cases were complicated by fe-brile neutropenia, mainly due to the brief duration of se-vere neutropenia (median 5 days, range 2–15). Hemato-logic toxicity was the main reason for treatment delays and dose reductions. Nineteen patients experienced treat-ment delays of more than 1 week duration, and 7 patients had a dose reduction. It has been reported that combina-tion chemotherapy regimens with either 2 or 3 agents led to similar rates of cytopenia in osteosarcoma [7–9] .

Nonhematological toxicity was rare and did not recur during subsequent treatment cycles. It is noteworthy that there was no major cardiac morbidity with longer follow-up. Absence of long-term cardiac toxicity renders it pos-sible to use higher doses of epirubicin. Cardiac toxicity is the dose-limiting toxicity of adriamycin, and prolonged perfusion of adriamycin is usually preferred to avoid car-diac morbidity. In our study, we aimed to increase the dose intensity of the anthracycline in the combination regimen and avoid cardiac toxicity by preferring epirubi-cin to adriamycin. Generally, early and late cardiac toxic-ity was not reported in the osteosarcoma literature [10–12] . Furthermore, cardiac toxicity was assessed only clin-ically in a majority of the previous reports [7, 8, 13] . It is important to note that osteosarcoma is a disease of the adolescence; therefore, cardiac toxicity might be under-estimated in the studies. Goorin et al. [3] reported that the rates of congestive heart failure and cardiac mortality were 5 and 2%, respectively, with anthracycline-based

regimens in osteosarcoma. We did not observe cardiac toxicity of greater than grade 2 detected by echocardiog-raphy and an electrocardiogram, with a median follow-up of 64 months in our study.

Most patients experienced some form of nonhemato-logical grade 3 or 4 toxicity including emesis, alopecia and fatigue. Cisplatin, ifosfamide and epirubicin combi-nation chemotherapy was highly emetogenic. A similar frequency of emesis and fatigue was observed in other series [10, 12, 13] .

Although the tumor size was large in most of the pa-tients, local relapse rates remained low, and furthermore, the limb-saving rate was high. The limb-saving rate re-mained high (76%) at 5 years compared with other stud-ies in the literature (limb-sparing surgery rates: range 50–79%) [2, 3, 14, 15] .

It has been known that the dose-dense or increased dose intensity concept is associated with higher response rates in osteosarcoma [7, 10–13, 16] . Histologic response to chemotherapy has been demonstrated to be a major prognostic indicator in osteosarcoma and is sometimes used as a surrogate marker of outcome [16–19] . The stud-ies from the Memorial Sloan-Kettering Cancer Center evaluated the efficacy of sequentially administered high-er doses of chemotherapeutic agents [16] . We evaluated the efficacy of higher doses of epirubicin and cisplatin together with ifosfamide administered concurrently. We have observed high response rates (complete plus good response rate of 63%) and high necrosis rates, but with a lower survival rate than expected. The 5-year overall sur-vival rate was between 60 and 75% in nonmetastatic os-teosarcoma patients in the European and North Ameri-can phase II trials [20–22] . While several studies support-ed the notion that higher response rates lead to prolonged survival, the results of the recently reported randomized European Osteosarcoma Intergroup trial suggested that increased dose intensity was associated with higher re-sponse rates; however, this has not been translated into a survival benefit [2] . Therefore, whether higher responses could predict improved survival could be argued today.

While we have also obtained high response rates, we could not achieve an improved 5-year survival outcome in our study. Similar overall survival rates were observed in a recently reported phase III trial (European Organiza-tion for Research and Treatment of Cancer, European Os-teosarcoma Intergroup trial). The reasons underlying this discrepancy might be the age of our study population which included patients above age 15 and the tumor size. Survival outcome of osteosarcoma is known to be better in the pediatric population. The Children’s Oncology

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Group, after conducting the largest multi-institutional randomized controlled trial in osteosarcoma using the 3-drug regimen of cisplatin, doxorubicin and high-dose methotrexate, reported 3-year progression-free survival and overall survival of 71 and 80%, respectively [23] . It has also been reported that larger tumor size was associ-ated with poor survival outcome [16] .

Given our data, we conclude that cisplatin, ifosfamide and epirubicin combination is an active regimen in terms

of response rate and is generally well tolerated in osteo-sarcoma. Chemotherapy-related toxicity was manage-able, without late cardiac toxicity and treatment-related death. Being able to use higher doses of epirubicin might be an advantage in the treatment of osteosarcoma. Our findings suggest that the efficacy of epirubicin contain-ing osteosarcoma regimens should be evaluated in the context of randomized trials in order to achieve higher response and survival rates.

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